The efficient delivery of therapeutic or diagnostic agents to cells presents a vexing problem for physicians in the treatment of patients. In some cases, therapeutic or diagnostic agents are active in vitro but are not clinically effective because the therapeutic or diagnostic agents do not penetrate into cells due to physical or chemical characteristics of the therapeutic or diagnostic agents such as charge, size, or other factors. In other cases, promising therapies await the discovery of efficient delivery vehicles.
One example of the latter case is gene therapy: gene medicines for the treatment of genetic diseases are being developed at a rapid pace but the ineffectiveness of present delivery vehicles has not allowed such medicines to be applied to treatable genetic diseases. The main problems for gene therapy are the lack of appropriate systems for transferring genes to an adequate number of target cells and the difficulty of obtaining consistent expression in particular target cells which is exacerbated by the low efficiency of expression in target cells.
Current gene therapy delivery technologies rely on recombinant viral gene vectors, direct injection of plasmids into tissue, air gun delivery of DNA coated pellets or liposome mediated gene transfer. These technologies have several liabilities which result in the aforementioned inadequacies. The liabilities of the current delivery methodologies include low efficiency, risk of neoplastic transformation due to insertion in the genome of a viral vector, risk of viral vector replication, immunogenic potential of the vectors noted above, and lack of cell specificity. Other drawbacks are associated with specific viral vectors, such as the lack of insertion of retroviral vectors in nondividing cells and inflammatory reactions resulting from the use of adenoviral vectors.
Certain classes of therapeutic or diagnostic agents must be administered in doses far in excess of doses needed for efficacy on a molecular level simply due to the lack of entry of the therapeutic or diagnostic agents into cells because of physicochemical properties of the therapeutic or diagnostic agents. The high doses necessary for efficacy, however, cannot always be administered because they can result in unwanted side effects such as systemic or tissue-specific toxicities.
Administration of therapeutic or diagnostic agents with an appropriate delivery vehicle can increase the effective concentration of a therapeutic or diagnostic agent at the site where the therapeutic or diagnostic agent is needed. With more efficient delivery of a therapeutic or diagnostic agent, systemic concentrations of the agent are reduced because lesser amounts of the therapeutic or diagnostic agent can be administered while accruing the same or better therapeutic results. Methodologies applicable to increased delivery efficiency of therapeutic or diagnostic agents typically focus on attaching a targeting moiety to the therapeutic or diagnostic agent or to a carrier which is subsequently loaded with a therapeutic or diagnostic agent. These methods suffer from the drawback that each therapeutic or diagnostic agent must be either bound to a targeting moiety or loaded into a carrier, which adds extra manufacturing and regulatory costs to the therapeutic or diagnostic agent. Binding a therapeutic agent to a targeting moiety also can alter if not destroy the activity of the therapeutic agent. Moreover, delivery of a therapeutic or diagnostic agent by such prior art methods requires pharmacies to maintain stocks of therapeutic and diagnostic agents with and without one or more delivery vehicles.
Targeted delivery of therapeutic or diagnostic agents has become an important goal of practitioners of the pharmaceutical arts to limit the aforementioned side effects. For example, chemotherapeutics for the treatment of cancers typically have side effects inseparable from their mode of action, i.e. cytotoxicity to dividing cells. Strategies for increasing the efficiency of delivery to reduce toxicity to normal tissues have centered on conjugation of chemotherapeutics to monoclonal antibodies specific for cancer cells. While such methods are an improvement over other prior art methods, each new conjugate must be carefully designed and tested for specificity and activity, and approved by the U.S. Food and Drug Administration. The conjugates also suffer from vastly increased size as compared to unconjugated therapeutic or diagnostic agents, which may hinder efficient delivery of the therapeutic or diagnostic agents to cells.
There is a need, therefore, for methods to increase the efficiency of unconjugated therapeutic or diagnostic agent delivery to all tissues of the body, regardless of the size, charge, or polarity of the therapeutic or diagnostic agents. Furthermore, there is a need for delivery of therapeutic or diagnostic agents to selected tissues or cells in the body without concomitant delivery to other tissues or cell types. There is also a need for a method of delivering therapeutic or diagnostic agents more efficiently that can be used with many kinds of existing therapeutic or diagnostic agents. There is a need to provide a method of targeted delivery of therapeutic or diagnostic agents which does not require conjugation or alteration of the therapeutic or diagnostic agents which are to be delivered. It is an object of the invention to fulfill these needs.
Thus, it is a general object of the invention to provide a method for increasing the efficiency of therapeutic or diagnostic agent delivery in vivo and in vitro.
It is another general object of the invention to provide a method for selectively delivering therapeutic or diagnostic agents to specific cells without delivery of those therapeutic or diagnostic agents to other cells.